Routinely, atopic diseases are allergic diseases, which can be divided in different categories, such as airborne allergies, food allergies and insect allergies, among others. The prevalence of allergic diseases is regularly increasing worldwide and represents a significant public health issue, especially in industrialized countries. For example, worldwide statistics from the American Academy of Allergy Asthma and Immunology shows for example that: allergic rhinitis affects between 10% and 30% of the population; insect (bees, wasps, fire ants) allergy fatal reactions occur in up to 50% of individuals who have no documented history of a previous systemic reaction; hive reaction occurs with lifetime prevalence above 20%.
The physiopathology underlying the allergic diseases described above involves immediate hypersensitivity reactions characterized by the production of IgE antibodies to the triggering allergen(s). These atopic or allergic reactions are thus defined as IgE-dependent. IgE-dependent allergic diseases are most often of respiratory origin, the allergens being airborn, such as pollen, house dust mite, animal fur, or of alimentary origin. Allergen-specific IgEs will bind to specific receptors on basophils and mastocytes that localize within the target tissue and, upon encounter with the allergen will liberate the contents of their granules and precipitate the allergic symptoms (Delespesse, 2012). Atopic diseases are also characterized by the involvement of adaptive immune responses that include Th2 lymphocytes, specific of the allergen(s) producing IL-4, IL-5 and IL-13.
Atopic diseases may be clearly distinguished from another clinical situation, whose underlying physiopathological mechanisms are totally distinct, that is delayed hypersensitivity. Examples of delayed hypersensitivity reactions are skin (or contact) allergic diseases and allergic diseases to different drugs. These delayed hypersensitivity reactions are IgE-independent. In hypersensitivity reactions the allergen is often a hapten. An IgE-independent allergic disease is characterized by the fact that the immunity response is indirect, since the hapten needs to be coupled to another cellular component from the host, usually a protein, in order to elicit an allergic reaction (Bach, 2012). In addition, another major physiopathological difference is that, delayed hypersensitivity reactions do not involve Th2 lymphocytes but rather Th1 lymphocytes that produce IL-2 and Interferon (IFN)γ.
To date, allergen immunotherapy is the only specific treatment that cures the underlying allergic disorder. Treating allergy, it also allows the improvement of pre-existent allergic condition, for example asthma and prevents the development of new sensitizations.
Nevertheless, allergic polysensitization is a frequent phenotype of allergic diseases, such as, for example, asthma.
Therefore, the importance of defining exactly the major allergen responsible of allergic symptoms before starting specific immunotherapy is essential. Moreover, there is a special interest in monitoring the severity of the allergic disease to provide an adapted treatment.
Currently, in vivo provocation tests are among the gold standards for diagnosis the occurrence of an allergic disease. A provocation test consists in exposing an individual to a suspicious allergen at increasing doses and monitoring the body's functions.
Numerous provocation tests are available and were described in the literature. Among them, bronchial provocation test, nasal provocation test, oral provocation test and skin provocation test are of special interest.
Skin provocation tests or skin allergy tests are widely used. These tests comprise intradermal (skin prick test) administration into the skin (usually the fore harm or the back) of very small quantities of an allergen in order to visualize directly an allergic reaction on the skin.
The non-specific bronchial provocation test is used to detect asymptomatic allergic asthma or to diagnose occupational asthma. In routine, the patient is exposed to a broncho-constrictor agent, usually a non-specific one such as histamine or methacholine. Following this exposure, the body's respiratory function is assessed by using a spirometer to measure the changes in the forced expiratory volume in one second, reflecting changes in lung function.
The specific bronchial provocation test and nasal provocation test, in which suspected allergens are administered, are the gold standards for diagnosis of, for example, mite allergy, but not routinely applied.
Following the same concept, the allergen can be provided to a patient throughout an oral administration to detect a food allergy. This is, for example, the case of cow's milk allergy in children.
Effectively, these provocation tests are invasive, require a qualified physician, are costly because of sophisticated materials, and most importantly may present risks, such as the occurrence of severe asthma exacerbation (for asthma) or anaphylaxis (for food allergy).
Hence, because they present well known risks, these tests are currently mainly used in clinical research within a hospital environment.
In vitro immunological tests routinely used are the determination of specific immunoglobulin E (IgE) that is indicative of the sensitization to an allergen but cannot allow the allergen to be identified. Moreover, increasing of IgE amount in IgE-dependent allergic diseases is often very limited, and therefore represents a poor biomarker for diagnosis.
The only functional test currently available is the basophil activation test (BAT), which relies upon quantification of alterations of specific activation markers on the surface or inside the basophil cells by flow cytometry. These changes can be detected and quantified on a single-cell basis using specific monoclonal antibodies coupled to a fluorochrome. However, this test has a low sensitivity and requires a divalent antigen, impairing its use for the diagnosis and/or monitoring of drug allergies.
In the field of IgE-independent allergic diseases, WO 02/073195 describes an in vitro test for diagnosing a nickel contact allergy. This test relies upon detecting cytokines that are released by T-cells after a hapten, nickel, has contacted said T-cells.
However, in the field of IgE-dependent allergic diseases there is still a need for a biomarker allowing the diagnosing or the monitoring of an allergic disease in an easy, sensitive, reproducible, and cost-effective manner.
Also, there is a need for a biomarker allowing the diagnosing or the monitoring of an IgE-dependent allergic disease and the determination of which being safe and non-invasive for patient.
There is a need of a biomarker, the determination of which being able to be correlated with the intensity of the symptoms associated with an IgE-dependent allergic disease.
In the field of IgE-dependent allergic disease diagnosing and/or monitoring, there is also a need to provide a biological test that is safe for the patient.
Moreover, there is a need to provide a biological test that is not invasive.
There is also a need to provide a biological test that is specific for a well-defined allergen able to elicit an IgE-dependent reaction.
There is also a need to provide a biological test that is cost effective, easy and rapid to execute.
In addition, there is a need to provide a biological test that is suitable for different categories of IgE-dependent allergic diseases or different allergens able to elicit an IgE-dependent reaction.
There is a need to provide a biological test that does not induce an anaphylactic reaction.
Finally, there is fundamental need to develop a biological test to diagnose and/or to monitor the severity of the condition of an IgE-dependent allergic disease.